CANCER PHARMACOLOGY PROGRAM PROJECT SUMMARY/ABSTRACT The Cancer Pharmacology (CP) Program has the overall goal to discover and develop more effective cancer treatments through pharmacology-based preclinical research. The ultimate aim is to improve patient outcomes through innovative and integrative research in cancer target biology, chemical biology, medicinal chemistry, pharmaceutics and biomedical engineering. Defining molecular functions of cancer targets and leveraging this knowledge to drive translational bench-to-bedside and bedside-to-bench research in drug discovery and delivery are signature Program features that span the Rutgers/Princeton Consortium. CP provide a platform for productive, collaborative and impactful science and discoveries. CP has 37 members from 18 Departments, 7 Schools, 2 Universities. The Program is well funded with $16.5M annual direct peer-reviewed grant support, $6.1M of which is cancer-focused (13 R01 equivalent, and 6 Multi-PI). CP members published 746 papers (up from 522 in 2004-10), 29% of which are collaborative (18% intra- and 18% inter-programmatic) with 22% in top-tier journals and 53% collaborative with other institutions. This represents an increase in both total and collaborative publications compared with last project period. Impactful science includes regulation of growth pathways by GRM1 in melanoma, novel mechanisms of amino acid signaling by mTOR in colorectal cancer, and epigenetic regulation in pediatric glioblastomas/sarcomas. CP members revealed key roles of mTOR and antioxidant pathways in cardiac protection and chronic pain management, which have implications for reducing cardiac toxicity, a dose-limiting side effect of chemo-therapy, and for improving analgesia in advanced stage cancer patients. Based on fundamental insights into the biology of molecular targets, CP members determined the mode of action for riluzole (a repurposed ALS drug) targeting GRM1 in melanoma and identified determining factors for therapeutic response for rapamycin. CP members focused on development of novel therapeutics and drug delivery technologies, and identified novel anticancer agents including a compound that restores mutant p53 function, BMI-1 inhibitors, and prodrugs for riluzole and the CINJ-developed topoisomerase 1 inhibitor Genz-644282. They developed innovative tumor-targeting nanocarriers containig multiple therapeutic modalities (small molecules, toxins, nucleic acids, and peptides/antibodies) and imaging enhancers (e.g., rare earth elements and Mn3O4), enabling cancer detection and treatment. CP members work with other CINJ Programs, particularly the Clinical Investigations and Precision Therapeutics Program (CIPT), to translate bench discoveries to clinical trials, contributing significantly to CINJ?s translational pipeline. They also use feedback from trials to gain further insight into target biology and mechanisms of treatment response for agents such as riluzole to improve therapeutic approaches.